TY - GEN
T1 - Quality of life, prognostic and predictive factors in vulnerable older patients with metastatic colorectal cancer receiving palliative chemotherapy
T2 - The randomized NORDIC9-study
AU - Liposits, Gabor
PY - 2024/3/13
Y1 - 2024/3/13
N2 - Colorectal cancer is accountable for the second highest mortality among all cancer types and
predominantly affects adults aged 70 years or older. Owing to the aging populations worldwide, the
number of older adults with cancer is steeply increasing including those with colorectal cancer.
Despite the majority of patients with metastatic colorectal cancer (mCRC) is older than 70 years, the
optimal treatment strategy is less clear due to the underrepresentation of older adults in randomized
controlled trials and very few clinical trials dedicated to this large group of patients.
The investigator-initiated randomized phase II study, the NORDIC9, prospectively tested an
approach among older patients with mCRC who were not considered being candidates for full-dose
combination treatment; reduced-dose combination vs full-dose single agent chemotherapy.
The NORDIC9-study included 160 patients from four Nordic countries between March 2015 and
October 2017 and established that reduced-dose combination chemotherapy resulted in significant
prolonged progression-free survival with a trend towards prolonged overall survival, fewer toxicities,
and hospital admissions compared to full-dose monotherapy. These encouraging results added
important knowledge to the literature and raised several questions regarding the patients' quality of
life and the potential prognostic and predictive factors in the NORDIC9 cohort. Therefore, we
conducted four sub-studies further investigating quality of life, the prognostic value of systemic
inflammation explored through plasma biomarkers, the prognostic value of physical functioning, and
the RAS/BRAF mutation status. Finally, we also explored the predictive value of treatment allocation
according to RAS/BRAF status.We found that patients receiving reduced-dose combination treatment maintained their quality of life
and physical performance and had lower symptom burden compared to the full-dose monotherapy
arm. The results of the biomarker analysis clearly demonstrated that patients who had elevated plasma
C-reactive protein (CRP) at inclusion had significant shorter overall survival and progression-free
survival than those with normal level of CRP, regardless of treatment.When analyzing survival outcomes according to physical performance, we found that Eastern
Cooperative Oncology Group performance status and Vulnerable Elderly Survey-13 were proper
tools to foresee shorter survival. These tools evaluate activities of daily living and instrumental
activities of daily living in different ways, although, patients with higher scores on these scales had
significantly higher risk for shorter survival.RAS/BRAF mutation status is a cornerstone of the therapeutic decision-making in young and fit adults
with mCRC; however, its real clinical impact on daily clinical practice is less known and its potential
role determining the use of targeted therapies is less established in older adults with mCRC.Our results demonstrate that patients whose mCRC was driven by BRAFV600E mutation had
significantly shorter overall survival and progression-free survival compared to patients presented
with other molecular sub-types. In this particular group of patients with BRAFV600E mutation, the use
of reduced-dose combination chemotherapy resulted in a remarkable overall survival advantage
compared to the full-dose monotherapy arm.I conclude that reduced-dose combination chemotherapy is the treatment of choice in older adults
with mCRC who are ineligible for intensive chemotherapy. Its use resulted in prolonged survival, less
toxicities, fewer hospital admissions, and preserved quality of life and physical performance. Using
biomarkers, measurements of physical functioning, and RAS/BRAF mutation status provide important
prognostic information and have therapeutic implication, thus, contribute to proper patient selection.
These factors may influence survival and enhance communication in the shared decision-making
process.
AB - Colorectal cancer is accountable for the second highest mortality among all cancer types and
predominantly affects adults aged 70 years or older. Owing to the aging populations worldwide, the
number of older adults with cancer is steeply increasing including those with colorectal cancer.
Despite the majority of patients with metastatic colorectal cancer (mCRC) is older than 70 years, the
optimal treatment strategy is less clear due to the underrepresentation of older adults in randomized
controlled trials and very few clinical trials dedicated to this large group of patients.
The investigator-initiated randomized phase II study, the NORDIC9, prospectively tested an
approach among older patients with mCRC who were not considered being candidates for full-dose
combination treatment; reduced-dose combination vs full-dose single agent chemotherapy.
The NORDIC9-study included 160 patients from four Nordic countries between March 2015 and
October 2017 and established that reduced-dose combination chemotherapy resulted in significant
prolonged progression-free survival with a trend towards prolonged overall survival, fewer toxicities,
and hospital admissions compared to full-dose monotherapy. These encouraging results added
important knowledge to the literature and raised several questions regarding the patients' quality of
life and the potential prognostic and predictive factors in the NORDIC9 cohort. Therefore, we
conducted four sub-studies further investigating quality of life, the prognostic value of systemic
inflammation explored through plasma biomarkers, the prognostic value of physical functioning, and
the RAS/BRAF mutation status. Finally, we also explored the predictive value of treatment allocation
according to RAS/BRAF status.We found that patients receiving reduced-dose combination treatment maintained their quality of life
and physical performance and had lower symptom burden compared to the full-dose monotherapy
arm. The results of the biomarker analysis clearly demonstrated that patients who had elevated plasma
C-reactive protein (CRP) at inclusion had significant shorter overall survival and progression-free
survival than those with normal level of CRP, regardless of treatment.When analyzing survival outcomes according to physical performance, we found that Eastern
Cooperative Oncology Group performance status and Vulnerable Elderly Survey-13 were proper
tools to foresee shorter survival. These tools evaluate activities of daily living and instrumental
activities of daily living in different ways, although, patients with higher scores on these scales had
significantly higher risk for shorter survival.RAS/BRAF mutation status is a cornerstone of the therapeutic decision-making in young and fit adults
with mCRC; however, its real clinical impact on daily clinical practice is less known and its potential
role determining the use of targeted therapies is less established in older adults with mCRC.Our results demonstrate that patients whose mCRC was driven by BRAFV600E mutation had
significantly shorter overall survival and progression-free survival compared to patients presented
with other molecular sub-types. In this particular group of patients with BRAFV600E mutation, the use
of reduced-dose combination chemotherapy resulted in a remarkable overall survival advantage
compared to the full-dose monotherapy arm.I conclude that reduced-dose combination chemotherapy is the treatment of choice in older adults
with mCRC who are ineligible for intensive chemotherapy. Its use resulted in prolonged survival, less
toxicities, fewer hospital admissions, and preserved quality of life and physical performance. Using
biomarkers, measurements of physical functioning, and RAS/BRAF mutation status provide important
prognostic information and have therapeutic implication, thus, contribute to proper patient selection.
These factors may influence survival and enhance communication in the shared decision-making
process.
U2 - 10.21996/bc8s-sx51
DO - 10.21996/bc8s-sx51
M3 - Ph.D. thesis
PB - Syddansk Universitet. Det Sundhedsvidenskabelige Fakultet
ER -